The prevalence of HIV-associated neurological disorders (HAND) is on the rise despite Highly Active Anti-Retroviral Therapy (HAART). The pathogenesis of HAND is primarily due to neurotoxic viral proteins such as HIV-1 gp120 and Tat due to the replication of HIV in the brain. Antiretrovirals have variable efficiencies in crossing he blood brain barrier and thus being unable to eliminate HIV-1 in the CNS or in reducing the neurotoxic viral proteins. To overcome this problem, we propose to employ a modular, aptamer-based approach to deliver therapeutics designed to neutralize HIV-1 and inhibit neurotoxic viral proteins hiding behind the blood brain barrier (BBB). We will develop the next generation of delivery agents that can transcytose the BBB, specifically target HIV and consequently achieve higher effective drug concentrations in the CNS to be able to combat and neutralize HIV-1 and its toxic byproducts. There will be two specific aims. In Aim 1, we will target HIV reservoirs in te CNS using previously selected anti-transferrin receptor (hTfR) aptamers that can cross an in vitro model BBB composed of Human Brain Microvascular Endothelial Cells (HBMECs). Using these aptamers and our in vitro BBB model, we will develop a strategy to deliver therapeutic antibodies, aptamers or other molecules across the BBB and attempt to neutralize recombinant gp120 or Tat protein-mediated neuronal killing or to prevent HIV-infection of macrophages. In Aim 2, using a novel cell-based SELEX approach (selective evolution of ligands by exponential amplification) and using a flow-based dynamic in vitro blood brain barrier (DIV-BBB; Flowcel Inc.) which accurately reproduces the BBB in vivo, we seek to identify RNA aptamers that can specifically cross the BBB and will subsequently adapt these for drug delivery across the BBB.